Proteasome inhibitors: A rational for clinical use in the treatment of multiple myeloma

Proteasome inhibitors (PI) represent the class of medicaments which lead to inhibition of catalytic chymotrypsin-like proteolytic proteasome subunits. Blockade of this specific structure drives to complete ubiquitin-proteasome machinery withdrawal. Total intracellular protein flow is regulated by the proteasome activity which acts through basal and signal activated proteolysis as the result of cell stimuli. Blockade of proteasome activity contribute to cell protein hyper concentration which results with activation of cell death mechanisms. This is primary endpoint of PI activity against the cancer cell. Multiple myeloma (MM) represents the second most frequent blood cancer. The backbone of therapy constitute of triple-combination of long-acting corticosteroid (dexamethason), imunomodulatory drugs (IMiDs), such as thalidomide, lenalidomideorpomalidomide, and PI. Treatment strategy involves the use of induction therapy, after which, if disease is sensitive, high dose therapy should be followed by autologous hematopoietic stem cell transplantation. The above-mentioned treatment modality is reserved for younger patients (≤65 years), while elderly have medical treatment without transplantation. Whether maintenance therapy should be applied after remission is achieved, remains a matter of great controversy, although many centers apply it as 'off label' use. Reversible PIs include: bortezomib and ixazomib, and irreversible PI include: carfilzomib, oprozomib and marizomib. These drugs are found to have tolerable safety profile with the accent on peripheral neuropathy, gastrointestinal and moderate hematological toxicityas the most usual adverse events. This article will consider clinical pharmacology of PIs.